Cipolla Research Identifies New Biomarker for Life-threatening Brain Injury during Preeclampsia

One of the three leading causes of maternal disease and death worldwide, preeclampsia occurs during the second half of pregnancy and is characterized by high blood pressure, protein in the urine, as well as swelling in the hands and face. The major maternal morbidity and mortality associated with preeclampsia is from brain injury. New research by Marilyn Cipolla, Ph.D., University of Vermont professor of neurological sciences, and colleagues sheds light on a new biomarker for brain injury in early-onset preeclampsia (EPE) – oxidized low-density lipoproteins (LDL).

The study appears in the March 2013 issue of The FASEB Journal.

In addition to kidney and cardiovascular damage, preeclampsia can lead to seizures (called eclampsia). According to Cipolla and her co-authors, neurological complications occur more often in EPE, in which delivery of the fetus occurs prior to 34 weeks of gestation and is viewed as more severe, than in late-onset preeclampsia (LPE). The only current “cure” for preeclampsia is delivery, which can be detrimental to the fetus if delivery is preterm.

Cipolla specializes in the blood-brain barrier (BBB) – a unique form of cells that line the many small blood vessels of the brain that is a selective barrier between the blood into the brain. She and former postdoctoral fellow Malou Schreurs, M.D., the first author on the study, were specifically interested in brain injury associated with preeclampsia and determining why this state could result in seizure.

To examine whether or not EPE plasma increases BBB permeability that could lead to seizure, the team used human blood plasma samples from normal pregnant, early-onset preeclamptic, and late-onset preeclamptic women to perfuse the cerebral vessels of nonpregnant rats.

While conducting this research, Schreurs described the EPE plasma as “gooey” to Cipolla, which provided the team with a clue to examine lipids, which are fats.

“Pregnancy is a physiologic state of hyperlipidemia,” says Cipolla. “When you add oxidative stress that occurs during preeclampsia, you get another form of low-density lipoprotein or oxidized LDL.” In the FASEB Journal article, she and her coauthors report that “BBB disruption in response to the EPE plasma was due to a 260 percent increase of circulating oxidized LDL binding to its receptor, LOX-1, and subsequent generation of peroxynitrite.”

Cipolla, who also has appointments in obstetrics, gynecology and reproductive sciences, as well as pharmacology, says the activation of LOX-1 is what causes the BBB permeability in response to high circulating oxLDL. In the future, she says, this process could be blocked at the early-onset stage, thus preventing an increase in permeability and the risk of seizure. Cipolla adds that having a biomarker for those at risk for brain injury could impact treatment and prevention options as well as delivery decisions in women with preeclampsia.

“Marilyn Cipolla’s identification of oxLDL as a diagnostic for the neurological form of preeclampsia has potential commercial uses as a diagnostic,” says Kerry Swift, M.S., technology licensing officer in the UVM Office of Technology Commercialization. “In addition, compounds that target LOX-1 could be potential therapeutics.”

In addition to Schreurs and Cipolla, coauthors on the study include Carl Hubel, Ph.D., and Arun Jeyabalan, M.D., of the Magee-Womens Research Institute at the University of Pittsburgh, and Ira Bernstein, M.D., professor and chair of obstetrics, gynecology and reproductive sciences at UVM.

Cipolla presented on the study’s findings at the Society for Gynecologic Investigation 2013 Annual Scientific Meeting March 20 to 23 in Orlando, Fla.